gw9662 and Encephalitis

In recent years, the role of angiotensin II (Ang II) and Ang II type 1 receptor (AT1) in the crosstalk between the immune system and the central nervous system has received more attention. The present study aimed to investigate the role of losartan, an AT1 receptor blocker, in the modulation of long-lasting adverse effects of repeated systemic lipopolysaccharide (LPS) injection in the brain function. For this purpose, 110 male BALB/c mice were administrated LPS (250 µg/kg) intraperitoneally (i.p.) for seven consecutive days. Mice were i.p. injected with losartan (1 and 3 mg/kg) three days before and during the LPS injection. To determine the role of PPAR-γ activation in the protective actions of losartan, GW9662, a PPAR-γ antagonist, was also co-administrated with losartan. Then, behavioral tests, including Morris water maze (MWM), novel object recognition test, passive avoidance, forced swim test (FST), elevated plus maze, and marble burying task, were conducted. The results demonstrated that losartan improved learning and memory impairment, attenuated anxiety-like behaviors, modulated brain inflammation and oxidative stress, and decreased amyloid-β accumulation. Losartan was unable to improve hippocampal BDNF and IL-10 levels as well as the retention trial in the MWM task and depressive-like behaviors. In addition, the PPAR-γ antagonist did not significantly influence the beneficial effects of losartan. Our findings suggest that AT1R blockade can protect the brain against most long-lasting hallmark effects of systemic inflammation. Also, based on the results, the beneficial actions of losartan were not mediated through PPAR-γ activation.

Topics: Amyloid beta-Peptides; Angiotensin Receptor Antagonists; Anilides; Animals; Anxiety; Behavior Rating Scale; Brain-Derived Neurotrophic Factor; Depression; Encephalitis; Hippocampus; Immunity, Innate; Injections, Intraperitoneal; Interleukin-10; Lipopolysaccharides; Losartan; Male; Memory Disorders; Mice; Mice, Inbred BALB C; Oxidative Stress; PPAR gamma

Opioid induced neuroinflammation is shown to be implicated in opioid analgesic tolerance development. In the present study the effect of pioglitazone on morphine-induced tolerance and neuroinflammation in the cerebral cortex of the rat was investigated.. Various groups of rats received morphine (10mg/kg; ip) and vehicle (po), or morphine (10mg/kg) and pioglitazone (20 or 40 mg/kg; po) once a day for 17 days. In order to determine the possible involvement of PPAR-γ in the pioglitazone effect, one group of rats received PPAR-γ antagonist, GW-9662 (2mg/kg; sc), and pioglitazone (40 mg/kg) and morphine once daily for 17 days. Nociception was assessed using a tail flick apparatus and the percentage of the maximal possible effect was calculated as well. On 18th day, 2h after the last morphine injection, the cerebral cortex of the animals were harvested and the tissue levels of tumour necrosis factor alpha, interleukin-1beta, interleukin-6, interleukin-10 and nuclear factor-kappa B activity were determined.. Co-administration of pioglitazone (40 mg/kg) with morphine not only attenuated morphine-induced tolerance, but also prevented the up-regulation of pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin-1beta, interleukin-6) and nuclear factor-kappa B activity in the rat cerebral cortex. Moreover, GW-9662 (2mg/kg) administration 30 min before pioglitazone, antagonized the above mentioned pioglitazone-induced effects.. It is concluded that oral administration of pioglitazone attenuates morphine-induced tolerance. This effect of pioglitazone may be, at least in part, due to its anti-inflammatory property which suppressed the cortical pro-inflammatory cytokine and inhibited of nuclear factor-kappa B activity.

Topics: Administration, Oral; Analgesics, Opioid; Anilides; Animals; Cerebral Cortex; Cytokines; Drug Tolerance; Encephalitis; Hypoglycemic Agents; Injections, Intraperitoneal; Male; Morphine; NF-kappa B; Pain Measurement; Pioglitazone; PPAR gamma; Rats; Rats, Wistar; Thiazolidinediones

In our previous studies, we found that a single ultralow dose of tetrahydrocannabinol (THC; 0.002 mg/kg, three to four orders of magnitude lower than the conventional doses) protects the brain from different insults that cause cognitive deficits. Because various insults may trigger a neuroinflammatory response that leads to secondary damage to the brain, the current study tested whether this extremely low dose of THC could protect the brain from inflammation-induced cognitive deficits. Mice received a single injection of THC (0.002 mg/kg) 48 hr before or 1-7 days after treatment with lipopolysccharide (LPS; 10 mg/kg) and were examined with the object recognition test 3 weeks later. LPS caused long-lasting cognitive deficits, whereas the application of THC before or after LPS protected the mice from this LPS-induced damage. The protective effect of THC was blocked by the cannabinoid (CB) 1 receptor antagonist SR14176A but not by the CB2 receptor antagonist SR141528 and was mimicked by the CB1 agonist ACEA but not by the CB2 agonist HU308. The protective effect of THC was also blocked by pretreatment with GW9662, indicating the involvement of peroxisome proliferator-activated receptor-γ. Biochemical examination of the brain revealed a long-term (at least 7 weeks) elevation of the prostaglandin-producing enzyme cyclooxygenase-2 in the hippocampus and in the frontal cortex following the injection of LPS. Pretreatment with the extremely low dose of THC tended to attenuate this elevation. Our results suggest that an ultralow dose of THC that lacks any psychotrophic activity protects the brain from neuroinflammation-induced cognitive damage and might be used as an effective drug for the treatment of neuroinflammatory conditions, including neurodegenerative diseases.

Topics: Anilides; Animals; Arachidonic Acids; Brain; Camphanes; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cognition Disorders; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Encephalitis; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; PPAR gamma; Pyrazoles; Recognition, Psychology

Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions.. We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662.. We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.. The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Anilides; Animals; Benzimidazoles; Benzoates; Brain; Cell Death; Disease Models, Animal; Dopaminergic Neurons; Encephalitis; Gene Expression Regulation; Lectins; Leukocyte Common Antigens; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; MPTP Poisoning; PPAR gamma; Receptor, Angiotensin, Type 1; Telmisartan; Tyrosine 3-Monooxygenase

Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcriptional factor that regulates lipid metabolism and inflammation. Behavioral sensitization is an experimental model of psychostimulant psychosis; it is elicited by repeated administration of psychostimulants and has recently been implicated in brain inflammation. We examined the involvement of PPARgamma, one of the isotypes of PPAR, in development of behavioral sensitization to the stimulant effect of methamphetamine (METH) (1 mg/kg, subcutaneously) in mice. Repeated administration of METH (once daily for 5 days) enhanced the locomotor-activating effect of METH, which was reproduced by METH challenge on withdrawal day 7 (test day 12). The protein level and the activity of PPARgamma were significantly increased in the nuclear fraction of whole brain after 5 days of METH administration (test day 5) and on withdrawal day 7 (test day 12). Both pioglitazone and ciglitazone (PPARgamma agonists; 0.5-5.0 microg, intracerebroventricularly (i.c.v.), once daily) prevented the expression of behavioral sensitization to METH challenge on withdrawal day 7, but not the sensitization that occurred during repeated administration of METH. In addition, the magnitude of expression of behavioral sensitization was augmented by treatments with GW9662 (a PPARgamma antagonist; 0.5-5.0 microg i.c.v., once daily) during the withdrawal period. The pioglitazone-induced alleviation of behavioral sensitization was synergistically facilitated by simultaneous i.c.v. injection of 9-cis-retinoic acid (1.0 microg), an agonist for the retinoid X receptor which is a ligand-activated nuclear receptor that forms heterodimers with PPAR. These results suggest that PPARgamma has a significant role in the expression of behavioral sensitization to METH in mice.

Topics: Amphetamine-Related Disorders; Anilides; Animals; Behavior, Animal; Brain; Brain Chemistry; Cell Nucleus; Disease Models, Animal; Dopamine Uptake Inhibitors; Electrophoretic Mobility Shift Assay; Encephalitis; Hypoglycemic Agents; Male; Methamphetamine; Mice; Mice, Inbred ICR; Motor Activity; Nucleus Accumbens; Pioglitazone; PPAR gamma; Psychoses, Substance-Induced; Retinoid X Receptors; Reward; Thiazolidinediones

Thiazolidinediones (TZDs) are synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). TZDs are known to curtail inflammation associated with peripheral organ ischemia. As inflammation precipitates the neuronal death after stroke, we tested the efficacy of TZDs in preventing brain damage following transient middle cerebral artery occlusion (MCAO) in adult rodents. As hypertension and diabetes complicate the stroke outcome, we also evaluated the efficacy of TZDs in hypertensive rats and type-2 diabetic mice subjected to transient MCAO. Pre-treatment as well as post-treatment with TZDs rosiglitazone and pioglitazone significantly decreased the infarct volume and neurological deficits in normotensive, normoglycemic, hypertensive and hyperglycemic rodents. Rosiglitazone neuroprotection was not enhanced by retinoic acid x receptor agonist 9-cis-retinoic acid, but was prevented by PPARgamma antagonist GW9662. Rosiglitazone significantly decreased the post-ischemic intercellular adhesion molecule-1 expression and extravasation of macrophages and neutrophils into brain. Rosiglitazone treatment curtailed the post-ischemic expression of the pro-inflammatory genes interleukin-1beta, interleukin-6, macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, cyclooxygenase-2, inducible nitric oxide synthase, early growth response-1, CCAAT/enhancer binding protein-beta and nuclear factor-kappa B, and increased the expression of the anti-oxidant enzymes catalase and copper/zinc-superoxide dismutase. Rosiglitazone also increased the expression of the anti-inflammatory gene suppressor of cytokine signaling-3 and prevented the phosphorylation of the transcription factor signal transducer and activator of transcription-3 after focal ischemia. Thus, PPARgamma activation with TZDs might be a potent therapeutic option for preventing inflammation and neuronal damage after stroke with promise in diabetic and hypertensive subjects.

Topics: Anilides; Animals; Cerebral Infarction; Chemotaxis, Leukocyte; Cytokines; Diabetes Mellitus, Type 2; Disease Models, Animal; Encephalitis; Hypertension; Intercellular Adhesion Molecule-1; Ischemic Attack, Transient; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neuroprotective Agents; Pioglitazone; PPAR gamma; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rosiglitazone; Superoxide Dismutase; Superoxide Dismutase-1; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thiazolidinediones